The leading candidate antigen for a Lyme disease vaccine, the Borrelia burgdorferi outer surface is protein A or OspA is currently in clinical testing in various formulations by three companies, among them MedImmune. A major concern for OspA-based vaccines is that antibodies against this protein are effective only if present at high levels prior to infection, suggesting that an infection-induced memory response to OspA will be of little or no benefit. After delivery by a tick bite B. burgdorferi establishes an initial infection in the dermis, a site rich in collagen fibers. It has recently been shown by B. Guo, M. Hook and collaborators that B. burgdorferi can bind to collagen fibers through adhesion to the collagen-associated proteoglycan decorin through interactions with the novel borrelia adhesin decorin binding protein A (DbpA). We have shown in Phase I of this study that DbpA: i) had efficacy as an experimental vaccine for Lyme disease, ii) had serologic conservation comparable to, or better than, OspA, and iii) was a target for protection on host-adapted spirochetes, unlike OspA. Additionally, in a small pilot experiment toward a Phase II study, rabbit anti-DbpA serum protected mice against borrelia challenge by tick bite. In Phase II of this study we propose to: 1) determine the number of DbpA seroprotective groups, 2) demonstrate that DbpA vaccines will elicit protection against tick-borne B. burgdorferi challenge in mice, 3) demonstrate that protective antibody responses to DbpA will be achieved in larger animals, including non-human primates, with clinically relevant adjuvants, and 4) identify the principal DbpA epitope(s) targeted by growth-inhibitory antibodies to facilitate optimization of vaccine delivery protocols. We further propose that vaccines based on DbpA may extend, or surpass, the efficacy of OspA-based vaccines. PROPOSED COMMERCIAL APPLICATION: No vaccine for Lyme disease is approved for human use, and immune responses to the approved veterinary vaccine are of limited duration. The lead candidate subunit vaccines now in trials may have limited efficacy in the field. The demand for an effective vaccine is very high, particularly in areas endemic for Lyme disease. The proposed studies will yield novel vaccine candidates that target in vivo expressed antigens, and that may extend, or surpass, the efficacy of the current Lyme vaccine candidate.